Figure 8.

Schematic diagram of proposed mechanisms underlying the regulation of innate immune response by influenza virus H5N1/HM M2 protein. Proton channel activity of M2 protein was essential for the increase of Ca²⁺ entry into cytoplasm from extracellular with a subsequent elevation in ROS production. On one hand, the increase level of ROS directly or indirectly led to the activation of ATG5 and inhibition of AKT and MTOR activity through the PI3K-AKT-MTOR pathway, thereby triggering M2-induced autophagy process. One the other hand, M2 protein anchored to the mitochondria, increased the mitochondrial number and accelerated the mitochondria fusion, which resulted in increasing ROS-dependent MAVS aggregations. The MAVS aggregates can be packed into the autophagosome and be degraded by the lysosomal enzyme in the process of autolysosome formation. LC3B and ATG5 interact with MAVS in this process, thereby attenuating MAVS-mediated antiviral signaling pathway. However, M2 physically interacted with MAVS and sequestered the MAVS-ATG5 and MAVS-LC3B complexes formation, thus leading to the release of MAVS aggregates from the ATG5-MAVS and LC3B-MAVS complexes. Furthermore, M2 protein inhibited the autolysosome formation, which suppressed the MAVS aggregates degradation. The released MAVS aggregates from ATG5-MAVS and LC3B-MAVS complexes in turn participated in the MAVS-mediated innate immune response, which resulted in subsequent amplification of IFN and inflammatory cytokine signaling by RLR signaling.